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1.
Science ; 367(6484): 1362-1366, 2020 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-32193325

RESUMO

Stimulants such as methylphenidate are increasingly used for cognitive enhancement but precise mechanisms are unknown. We found that methylphenidate boosts willingness to expend cognitive effort by altering the benefit-to-cost ratio of cognitive work. Willingness to expend effort was greater for participants with higher striatal dopamine synthesis capacity, whereas methylphenidate and sulpiride, a selective D2 receptor antagonist, increased cognitive motivation more for participants with lower synthesis capacity. A sequential sampling model informed by momentary gaze revealed that decisions to expend effort are related to amplification of benefit-versus-cost information attended early in the decision process, whereas the effect of benefits is strengthened with higher synthesis capacity and by methylphenidate. These findings demonstrate that methylphenidate boosts the perceived benefits versus costs of cognitive effort by modulating striatal dopamine signaling.


Assuntos
Cognição/efeitos dos fármacos , Corpo Estriado/metabolismo , Dopamina/metabolismo , Metilfenidato/farmacologia , Motivação/efeitos dos fármacos , Sulpirida/farmacologia , Adolescente , Núcleo Caudado/metabolismo , Comportamento de Escolha , Tomada de Decisões , Dopamina/biossíntese , Antagonistas dos Receptores de Dopamina D2/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Feminino , Fixação Ocular , Humanos , Masculino , Memória , Recompensa , Movimentos Sacádicos , Transdução de Sinais/efeitos dos fármacos , Adulto Jovem
2.
Braz J Otorhinolaryngol ; 86(1): 83-90, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30482521

RESUMO

INTRODUCTION: Subjective benign paroxysmal positional vertigo is a form of benign paroxysmal positional vertigo in which during the diagnostic positional maneuvers patients only present vertigo symptoms with no nystagmus. OBJECTIVE: To study the characteristics of subjects with subjective benign paroxysmal positional vertigo. METHODS: Prospective multicenter case-control study. All patients presenting with vertigo in the Dix-Hallpike test that presented to the participating hospitals were included. The patients were separated into two groups depending on whether nystagmus was present or not. An Epley Maneuver of the affected side was performed. In the follow-up visit, patients were checked to see if nystagmus and vertigo were present. Both groups of patients were compared to assess the success rate of the Epley maneuver and also to compare the presence of 19 variables. RESULTS: 259 patients were recruited, of which 64 belonged to the subjective group. Nystagmus was eliminated in 67.2% of the patients with benign paroxysmal positional vertigo. 89.1% of the patients with subjective benign paroxysmal positional vertigo remained unaffected by nystagmus, thus showing a significant difference (p=0.001). Osteoporosis and migraine were the variables which reached the closest to the significance level. In those patients who were taking vestibular suppressors, the percentage of subjective benign paroxysmal positional vertigo was not significantly higher. CONCLUSIONS: Subjective benign paroxysmal positional vertigo should be treated using the Epley maneuver. More studies are needed to establish a relationship between osteoporosis, migraine and subjective benign paroxysmal positional vertigo. The use of vestibular suppressants does not affect the detection of nystagmus.


Assuntos
Vertigem Posicional Paroxística Benigna/fisiopatologia , Transtornos de Enxaqueca/fisiopatologia , Osteoporose/fisiopatologia , Adolescente , Adulto , Vertigem Posicional Paroxística Benigna/complicações , Vertigem Posicional Paroxística Benigna/tratamento farmacológico , beta-Histina/uso terapêutico , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/complicações , Nistagmo Fisiológico/fisiologia , Osteoporose/complicações , Modalidades de Fisioterapia , Postura/fisiologia , Estudos Prospectivos , Sulpirida/uso terapêutico , Adulto Jovem
3.
J Pharmacol Sci ; 142(1): 26-33, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31786058

RESUMO

Cedrol, mainly derived from Juniperus virginiana L. essential oil, has been demonstrated the anxiolytic effect, although its mechanism of action is still not fully established. In the present study, male ICR mice were submitted to the elevated plus maze (EPM) and light-dark box (LDB) tests to investigate the putative mechanism of anxiolytic effect. WAY100635 (5-HT1A receptor antagonist), flumazenil (benzodiazepine receptor antagonist), SCH23390 (dopamine D1 receptor antagonist) or sulpiride (dopamine D2/D3 receptor antagonist) were used in the behavioral experiment to determine the mechanism of action of cedrol. Subsequently, the monoamine neurotransmitter levels were evaluated after behavioral tests. The data suggest that no significant effect in behavioral parameters were observed after sole intraperitoneal (i.p.) injection of antagonists compared to saline group. The anxiolytic effect of cedrol in behavioral procedures was blocked by either WAY100635 or flumazenil. The anxiolytic effect of cedrol (1200 mg/kg) was effectively antagonized by SCH23390 (0.125 mg/kg). Furthermore, cedrol decreased the DA and NE levels in hippocampus, striatum and hypothalamus. The present findings suggest that the dopaminergic system (D1 receptor) rather than serotoninergic or GABAergic system may potentially be involved in the modulation of cedrol-induced anxiolytic-like behaviors in mice.


Assuntos
Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Sesquiterpenos Policíclicos/farmacologia , Receptores Dopaminérgicos/metabolismo , Animais , Benzazepinas/farmacologia , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Flumazenil/farmacologia , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos ICR , Norepinefrina/metabolismo , Piperazinas/farmacologia , Piridinas/farmacologia , Antagonistas da Serotonina/farmacologia , Sulpirida/farmacologia
4.
J Physiol Sci ; 69(6): 1019-1028, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31664642

RESUMO

We aimed to identify the neurotransmitters and brain regions involved in exercise efficiency in mice during continuous complicated exercises. Male C57BL/6J mice practiced treadmill running with intermittent obstacles on a treadmill for 8 days. Oxygen uptake (VO2) during treadmill running was measured as exercise efficiency. After obstacle exercise training, the VO2 measured during treadmill running with obstacles decreased significantly. Obstacle exercise-induced c-Fos expressions and dopamine turnover (DOPAC/dopamine) in the septum after obstacle exercise training were significantly higher than that before training. The dopamine turnover was correlated with exercise efficiency on the 3rd day after exercise training. Furthermore, the training effect on exercise efficiency was significantly decreased by injection of dopamine receptor antagonists into the septum and was associated with decreased c-Fos expressions in the septum and hippocampus of the mice. These results suggest that dopaminergic function in the septum is involved in exercise efficiency during continuous complicated exercises.


Assuntos
Dopamina/farmacologia , Consumo de Oxigênio/fisiologia , Condicionamento Físico Animal/fisiologia , Septo do Cérebro/efeitos dos fármacos , Animais , Benzazepinas/farmacologia , Biomarcadores , Antagonistas de Dopamina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Genes fos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Dopamina D1/antagonistas & inibidores , Corrida , Serotonina/metabolismo , Sulpirida/farmacologia
5.
Bull Exp Biol Med ; 167(6): 809-812, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31656010

RESUMO

Prostatotropic activity of (3,5-dimethyl-4-hydroxy)benzyl thiododecane (T-DD) was evaluated on a model of benign prostatic hyperplasia induced in Wistar rats by chronic (2 months) intraperitoneal administration of sulpiride (40 mg/kg). Morphometric analysis of the dorsolateral lobe of the prostate showed that after the 2-month course of intragastric T-DD (100 mg/kg) administered in parallel with sulpiride, the volume density of glandular epithelium decreased by 1.7 times, while the volume density of prostate stroma increased by 2 times. After administration of the reference drug Permixon at a dose of 50 mg/kg, the volume densities of epithelium decreased by 1.3 times and stromal volume density increased by 1.5 times. The observed effects are presumably related to suppression of 5α-reductase activity and modulation of estrogen receptors in the prostate.


Assuntos
Próstata/efeitos dos fármacos , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/patologia , Agentes Urológicos/uso terapêutico , Animais , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Masculino , Tamanho do Órgão/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Próstata/patologia , Hiperplasia Prostática/induzido quimicamente , Ratos , Ratos Wistar , Sulpirida , Agentes Urológicos/química
6.
Bull Exp Biol Med ; 167(5): 606-609, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31606803

RESUMO

Experimental model of sulpiride-provoked benign prostatic hyperplasia was employed to comparatively assess the effect of phenolic antioxidants (dihydroquercetin, p-thyrozol, dibornol, and prostagenin) on prostate morphology. All examined agents decreased the degree of hyperplasia in acinar epithelium; the greatest efficacy was demonstrated by prostagenin. Moreover, dihydroquercetin and p-thyrozol increased the cross-section area of acinar lumina and prostate volume, which is inadmissible in this pathology. These results suggest that the use of phenolic antioxidants in the therapy of benign prostatic hyperplasia should be strictly controlled.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Metimazol/farmacologia , Fenóis/farmacologia , Hiperplasia Prostática/tratamento farmacológico , Quercetina/análogos & derivados , Células Acinares/efeitos dos fármacos , Células Acinares/patologia , Animais , Animais não Endogâmicos , Modelos Animais de Doenças , Humanos , Masculino , Tamanho do Órgão/efeitos dos fármacos , Próstata/efeitos dos fármacos , Próstata/patologia , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/patologia , Quercetina/farmacologia , Ratos , Sulpirida/administração & dosagem
7.
PLoS Negl Trop Dis ; 13(8): e0007573, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31408466

RESUMO

The metacercariae of the Clonorchis sinensis liver fluke excyst in the duodenum of mammalian hosts, and the newly excysted juveniles (CsNEJs) migrate along the bile duct via bile chemotaxis. Cholic acid is a major component of bile that induces this migration. We investigated the neuronal control of chemotactic behavior of CsNEJs toward cholic acid. The migration of CsNEJs was strongly inhibited at sub-micromolar concentration by dopamine D1 (LE-300 and SKF-83566), D2 (spiramide, nemonapride, and sulpiride), and D3 (GR-103691 and NGB-2904) receptor antagonists, as well as a dopamine reuptake inhibitor (BTCP). Neuropeptides, FMRFamide, peptide YY, and neuropeptide Y were also potent inhibitors of chemotaxis. Meanwhile, serotonergic, glutamatergic, and cholinergic inhibitors did not affect chemotaxis, with the exception of fluoxetine and CNQX. Confocal immunofluorescence analysis indicated that dopaminergic and cholinergic neurons were colocalized in the somatic muscle tissues of adult C. sinensis. Our findings suggest that dopaminergic neurons and neuropeptides play a major role in the chemotactic migration of CsNEJs to bile, and their inhibitors or modulators could be utilized to prevent their migration from the bile duct.


Assuntos
Quimiotaxia/efeitos dos fármacos , Quimiotaxia/fisiologia , Clonorchis sinensis/efeitos dos fármacos , Clonorchis sinensis/fisiologia , Fasciola hepatica/efeitos dos fármacos , Neurotransmissores/farmacologia , Animais , Benzamidas/farmacologia , Compostos de Bifenilo/farmacologia , Ácido Cólico , Dopamina/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Fármacos Atuantes sobre Aminoácidos Excitatórios/farmacologia , FMRFamida/farmacologia , Fluorenos/farmacologia , Neuropeptídeo Y/farmacologia , Peptídeo YY/farmacologia , Piperazinas/farmacologia , Serotoninérgicos/farmacologia , Compostos de Espiro/farmacologia , Sulpirida/farmacologia
8.
Behav Neurosci ; 133(6): 556-562, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31424230

RESUMO

Previous studies on drug abuse have shown that response to drug-associated cues exist during prolonged abstinence. In succession to previous investigations in our laboratory on morphine dependence and our research on acquisition and expression phases of morphine-conditioned place preference (CPP), in this study we attempt to determine the effects of intraaccumbal administration of SCH-23390, as a D1-like receptor antagonist, and sulpiride, as a D2-like receptor antagonist, in the maintenance of morphine-induced CPP in rats. Seventy-nine adult male Wistar rats weighing 200-280 g were bilaterally implanted with cannulas into the nucleus accumbens. During the 3-day conditioning phase, the animals received daily subcutaneous administration of morphine (5 mg/kg). CPP score and locomotor activity of animals were recorded by Ethovision software. Different doses (0.25, 1, 4 µg per 0.5 µL vehicle) of D1- and D2-like antagonists were bilateral injected daily after the expression phase and during the extinction phase. Our findings revealed that intraaccumbal administration of D1-like and D2-like antagonists after the CPP test shortened the extinction phase in the rats. The results suggested that the existence of the dopamine receptors in the nucleus accumbens was important for the maintenance of morphine-rewarding properties during the extinction phase. Therefore, dopamine receptors may be considered as a promising therapeutic agent in preventing the maintenance of morphine-rewarding effects in dependent individuals. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Assuntos
Núcleo Accumbens/efeitos dos fármacos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Analgésicos Opioides/farmacologia , Animais , Benzazepinas , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Psicológico , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Comportamento de Procura de Droga/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Masculino , Morfina/administração & dosagem , Morfina/farmacologia , Entorpecentes/farmacologia , Núcleo Accumbens/metabolismo , Ratos , Ratos Wistar , Receptores de Dopamina D1/antagonistas & inibidores , Recompensa , Sulpirida
9.
Behav Neurosci ; 133(6): 545-555, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31414832

RESUMO

Addiction to opioids is an important global problem. Published research has indicated the powerful rewarding effects of drug use, which in the case of opiates like morphine may lead to drug addiction and maladaptive decision making with negative social consequences. In-depth comprehension of the role of responsible mechanisms in addiction can lead us to better and more effective treatments for drug dependence. Continuing previous work in our laboratory, in this study we aimed to investigate the role of dopamine D1- and D2-like receptors in the dentate gyrus (DG) on the reinstatement of drug-seeking behavior induced by the combination of forced swim stress and a subthreshold dose of morphine on extinguished morphine-conditioned place preference in rats. The rats were bilaterally implanted with 2 separate cannulas into the DG region. After the extinction phase of morphine-conditioned place preference, the animals received different doses (0.5, 2, and 4 µg per 0.5 µL vehicle/side) of SCH-23390 or sulpiride on the reinstatement day and were tested for the combination of forced swim stress and a subthreshold dose of morphine in discrete groups. Our findings indicated that D1- and D2-like receptor antagonists attenuated the reinstatement induced by the combination of FSS and the subthreshold dose of morphine. The reduction was more robust in groups of animals that received sulpiride as compared with SCH-23390. Our results showed a role for DG dopamine receptors in relapse to drugs of abuse, the activity of which may be induced by exposure to a stressor like forced swim stress. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Assuntos
Giro Denteado/efeitos dos fármacos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Analgésicos Opioides/farmacologia , Animais , Benzazepinas/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Psicológico , Giro Denteado/metabolismo , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Comportamento de Procura de Droga/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Morfina/farmacologia , Entorpecentes/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de Dopamina D1/antagonistas & inibidores , Recompensa , Estresse Psicológico , Sulpirida/farmacologia , Natação
10.
J UOEH ; 41(2): 231-237, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31292369

RESUMO

We had a forensic autopsy case in which drugs were detected in a cadaver that had been stored in a cold and wet condition for 5 years. The skin of the cadaver was hard, and the color was partly whitish or dark brown. Though the cadaver had transformed into adipocere in the wet and cold condition, QuEChERS extraction and LC-MS/MS revealed the presence of sulpiride and estazolam in the femoral muscle and bone marrow. The concentrations of sulpiride and estazolam in the femoral muscle were 10.6 ng/g and 39.9 ng/g, respectively. The result of a drug screening test led not only to the cause of death but also to the personal identification of the cadaver. The individual had a history of drug taking, which had been stored in his medical records at the hospital for a long time. The fact of taking sulpiride and estazolam at the same time was characteristic, and it was useful in identifying the cadaver in this case. The progress in analytical technology has made possible the detection of particle drugs from old or adipoceratous cadavers, but there have been no reports of particle drugs being detected in a cadaver that had been dead for 5 years and had transformed to adipocere, as in our present case. The analytical results by LC-MS/MS were certainly important for the diagnosis of the cause of death, and, moreover, they were useful for the purpose of personal identification.


Assuntos
Ansiolíticos/análise , Antipsicóticos/análise , Autopsia , Cadáver , Cromatografia Líquida/métodos , Estazolam/análise , Medicina Legal/métodos , Mudanças Depois da Morte , Sulpirida/análise , Espectrometria de Massas em Tandem/métodos , Ansiolíticos/isolamento & purificação , Antipsicóticos/isolamento & purificação , Estazolam/isolamento & purificação , Humanos , Masculino , Músculo Esquelético/química , Sulpirida/isolamento & purificação , Fatores de Tempo
11.
Yonsei Med J ; 60(8): 760-767, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31347331

RESUMO

PURPOSE: Discontinuation of offending drugs can prevent drug-induced parkinsonism (DIP) before it occurs and reverse or cure it afterwards. The aim of this study was to investigate the prevalence of DIP and the utilization of offending drugs through an analysis of representative nationwide claims data. MATERIALS AND METHODS: We selected DIP patients of ages ranging from 40 to 100 years old with the G21.1 code from the Korean National Service Health Insurance Claims database from 2009 to 2015. The annual standardized prevalence of DIP was explored from 2009 to 2015. Trends were estimated using the compound annual growth rate (CAGR) and the Cochran-Armitage test for DIP over the course of 6 years. Additionally, the utilization of offending drugs was analyzed. RESULTS: The annual prevalence of DIP was 4.09 per 100000 people in 2009 and 7.02 in 2015 (CAGR: 9.42%, p<0.001). Levosulpiride use before and after DIP diagnosis showed a clear trend for decreasing utilization (CAGR: -5.4%, -4.3% respectively), whereas the CAGR for itopride and metoclopramide increased by 12.7% and 6.4%, respectively. In 2015, approximately 46.6% (858/1840 persons) of DIP patients were prescribed offending drugs after DIP diagnosis. The most commonly prescribed causative drug after DIP diagnosis was levosulpiride. CONCLUSION: The prevalence of DIP has increased. To prevent or decrease DIP, we suggest that physicians reduce prescriptions of benzamide derivatives that have been most commonly used, and that attempts be made to find other alternative drugs. Additionally, the need for continuing education about offending drugs should be emphasized.


Assuntos
Doença de Parkinson Secundária/epidemiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Benzamidas/efeitos adversos , Compostos de Benzil/efeitos adversos , Prescrições de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson Secundária/diagnóstico , Prevalência , República da Coreia/epidemiologia , Sulpirida/efeitos adversos , Sulpirida/análogos & derivados , Adulto Jovem
12.
Acta Pharmacol Sin ; 40(12): 1596-1602, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31165782

RESUMO

Previous studies show that dopamine D2-like receptor (D2DR) antagonist sulpiride (SUL) enhances the antitumor efficacy of dexamethasone (DEX) in drug-resistant breast cancer involving cancer stem-like cells (CSCs). In this study, we investigated the pharmacokinetic (PK) properties of SUL in nude mice and developed a semi-mechanism PK/PD model to quantitatively characterize the synergistic effect of DEX and SUL in preclinical breast cancer xenografts. After nude mice received oral administration of a single dose of SUL (50 mg/kg, ig), plasma concentrations were assessed using LC-MS/MS. A two-compartment model with double first-order absorption rate was developed to describe the PK profiles of SUL. The pharmacodynamic (PD) study was conducted in nude mice bearing human breast cancer MCF-7/Adr xenografts, which received oral administration of DEX (1, 8 mg·kg-1·d-1) or SUL (25, 50 mg·kg-1·d-1) alone or in various combination. Tumor volumes were measured every other day. The PK model of SUL as well as that of DEX with a time-dependent clearance were integrated into the final PK/PD model both using Hill's function, where DEX exerted its antitumor efficacy by inhibiting the proliferation of tumor cells, and SUL enhanced DEX responses by decreasing the sensitivity parameter EC50. The PK/PD model was evaluated and subjected external validation. Finally, simulations were performed to predict the antitumor efficacy of DEX combined with SUL under various dose regimens, where changing dosing frequency of SUL had little effect, while the antitumor efficacy was predicted to be improved when DEX was given more frequently. The established PK/PD model in this study quantitatively characterizes the antitumor efficacy of the DEX combined with SUL as well as their synergism, and the simulations could provide reference for dose optimization of the combination in future studies.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Dexametasona/uso terapêutico , Sulpirida/uso terapêutico , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Dexametasona/farmacocinética , Dexametasona/farmacologia , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Feminino , Humanos , Camundongos Nus , Modelos Biológicos , Sulpirida/farmacocinética , Sulpirida/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
13.
J Vet Pharmacol Ther ; 42(4): 440-446, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31206720

RESUMO

Levosulpiride (LSP) is the l-enantiomer of sulpiride, and LSP recently replacing sulpiride in several EU countries. Several studies about LSP in humans are present in the literature, but neither pharmacodynamic nor pharmacokinetic data of LSP is present for veterinary species. The aim of this study was to assess the pharmacokinetic profile of LSP after intravenous (IV), intramuscular (IM), and oral (PO) administration in goats. Animals (n = 6) were treated with 50 mg LSP by IV, IM, and PO routes according to a randomized cross-over design (3 × 3 Latin-square). Blood samples were collected prior and up to 24 hr after LSP administration and quantified using a validated HPLC method with fluorescence detection. IV and IM administration gave similar concentration versus time curve profiles. The IM mean bioavailability was 66.97%. After PO administration, the drug plasma concentrations were detectable only in the time range 1.5-4 hr, and the bioavailability (4.73%) was low. When the AUC was related to the administered dose in mg/kg, there was a good correlation in the IV and IM groups, but very low correlation for the PO route. In conclusion, the IM and IV administrations result in very similar plasma concentrations. Oral dosing of LSP in goats is probably not viable as its oral bioavailability was very low.


Assuntos
Cabras/sangue , Sulpirida/análogos & derivados , Animais , Área Sob a Curva , Estudos Cross-Over , Antagonistas de Dopamina/administração & dosagem , Antagonistas de Dopamina/farmacocinética , Vias de Administração de Medicamentos , Feminino , Meia-Vida , Sulpirida/administração & dosagem , Sulpirida/farmacocinética
15.
Biomol Concepts ; 10(1): 51-61, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30956225

RESUMO

The antidepressant-like effects of zinc (Zn) have been documented in some animal models of depression. In addition, antidepressants may reduce the abuse potential of opioids by affecting their rewarding effect. Hence, this study was performed to investigate the effect of Zn on the expression of morphine-induced conditioned place preference (CPP) in male rats. We used an unbiased CPP paradigm for investigating the effect of Zn. The intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administrations of Zn (5-20 mg/kg, i.p., and 10 nmol/rat, respectively) with or without morphine did not induce conditioned place aversion (CPA) or CPP during acquisition phase. However, the same i.p. and i.c.v. administrations of Zn induced morphine-like CPP in the expression phase. Pre-treatment with dopamine receptor antagonists (SCH23390, sulpiride, and haloperidol) and serotonin receptor antagonists (WAY100135, ketanserin, and ondansetron) reversed the enhancement effect of Zn on the expression of morphine-induced CPP (especially 20mg/kg, i.p. and 10 nmol/rat, i.c.v.). These findings suggest that acute i.p. and i.c.v administration of Zn might enhance the rewarding properties of morphine through involvement with dopaminergic and serotonergic neuronal systems.


Assuntos
Condicionamento Psicológico/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Morfina/farmacologia , Antagonistas da Serotonina/farmacologia , Zinco/farmacologia , Animais , Benzazepinas/farmacologia , Haloperidol/farmacologia , Ketanserina/farmacologia , Masculino , Ondansetron/farmacologia , Piperazinas/farmacologia , Ratos , Ratos Wistar , Recompensa , Sulpirida/farmacologia
16.
Chem Biol Interact ; 305: 134-147, 2019 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-30922767

RESUMO

Methiopropamine (MPA) is structurally categorized as a thiophene ring-based methamphetamine (MA) derivative. Although abusive potential of MPA was recognized, little is known about the neurotoxic potential of MPA up to now. We investigated whether MPA induces dopaminergic neurotoxicity, and whether MPA activates a specific dopamine receptor. Here, we observed that treatment with MPA resulted in dopaminergic neurotoxicity in a dose-dependent manner. MPA treatment potentiated oxidative parameters (i.e., increases in the level of reactive oxygen species, 4-hydroxynonenal, and protein carbonyl), M1 phenotype-related microglial activity, and pro-apoptotic property (i.e., increases in Bax- and cleaved caspase-3-expressions, while a decrease in Bcl-2-expression). Moreover, treatment with MPA resulted in significant impairments in dopaminergic parameters [i.e., changes in dopamine level, dopamine turnover rate, tyrosine hydroxylase (TH) levels, dopamine transporter (DAT) expression, and vesicular monoamine transporter-2 (VMAT-2) expression], and in behavioral deficits. Both dopamine D1 receptor antagonist SCH23390 and D2 receptor antagonist sulpiride protected from these neurotoxic consequences. Therefore, our results suggest that dopamine D1 and D2 receptors simultaneously mediate MPA-induced dopaminergic neurodegeneration in mice via oxidative burdens, microgliosis, and pro-apoptosis.


Assuntos
Metanfetamina/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Benzazepinas/farmacologia , Benzazepinas/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Dopamina/metabolismo , Antagonistas dos Receptores de Dopamina D2/farmacologia , Antagonistas dos Receptores de Dopamina D2/uso terapêutico , Febre/prevenção & controle , Locomoção/efeitos dos fármacos , Masculino , Metanfetamina/síntese química , Metanfetamina/química , Camundongos , Camundongos Endogâmicos ICR , Microglia/citologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D2/química , Sulpirida/farmacologia , Sulpirida/uso terapêutico , Tirosina 3-Mono-Oxigenase/metabolismo
17.
Artigo em Inglês | MEDLINE | ID: mdl-30783552

RESUMO

Background: Camptocormia is defined as forward flexion of the spine that manifests during walking and standing and disappears in recumbent position. The various etiologies include idiopathic Parkinson's disease, multiple system atrophy, myopathies, degenerative joint disease, and drugs. Case Report: A 67-year-old diabetic female presented with bradykinesia and camptocormia that started 1 year prior to presentation. Evaluation revealed levosulpiride, a dopamine receptor blocker commonly used for dyspepsia, to be the culprit. Discussion: It is well known that dopamine receptor blockers cause parkinsonism and tardive syndromes. We report a rare and unusual presentation of camptocormia attributed to this commonly used gastrointestinal drug in the Asian population.


Assuntos
Antagonistas de Dopamina/efeitos adversos , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/etiologia , Transtornos Parkinsonianos/diagnóstico , Transtornos Parkinsonianos/etiologia , Curvaturas da Coluna Vertebral/diagnóstico , Curvaturas da Coluna Vertebral/etiologia , Sulpirida/análogos & derivados , Idoso , Encéfalo/diagnóstico por imagem , Complicações do Diabetes , Diagnóstico Diferencial , Dispepsia/tratamento farmacológico , Feminino , Humanos , Atrofia Muscular Espinal/diagnóstico por imagem , Atrofia Muscular Espinal/tratamento farmacológico , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/tratamento farmacológico , Curvaturas da Coluna Vertebral/diagnóstico por imagem , Curvaturas da Coluna Vertebral/tratamento farmacológico , Sulpirida/efeitos adversos
18.
Anal Chim Acta ; 1049: 105-114, 2019 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-30612641

RESUMO

In this study, a novel two dimensional liquid chromatography - mass spectrometry (2D-LC-MS) method with use of a weak anion exchange column between the 1st DLC RP column and the 2nd DLC RP column (RP1-WAX-RP2) was developed and applied to identify drug impurities from MS incompatible mobile phases containing sodium 1-octanesulfonate and non-volatile buffer. The 1st DLC conditions follow exactly the original standard HPLC method recorded in Chinese Pharmacopeia (ChP), European Pharmacopeia (EP) or US Pharmacopeia (USP). An impurity fraction was collected with a built-in sample loop (100 µL) and transferred to the WAX column where 1-octanesulfonate and phosphate were trapped and removed. While, the impurity and other cations were eluted to the 2nd D column (RP2) for separation and identification by connected IT-TOF MS. Methods were programmed and applied to identify impurities in two generic drugs, sulpiride (hydrophilic drug with logP 0.57) and dobutamine (hydrophobic drug with logP 3.6). The results indicate that the methods based on RP1-WAX-RP2 column configuration offer a feasible solution for direct impurity identification in generic drug product or API without needs of off-line desalting from the MS incompatible mobile phases containing ion-pairing reagent and non-volatile buffer.


Assuntos
Cromatografia por Troca Iônica/métodos , Dobutamina/análise , Contaminação de Medicamentos , Espectrometria de Massas por Ionização por Electrospray/métodos , Sulpirida/análise , Cromatografia Líquida de Alta Pressão , Cromatografia de Fase Reversa/métodos
20.
J Gastroenterol Hepatol ; 34(1): 186-193, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29966173

RESUMO

BACKGROUND AND AIM: Metformin has been shown to have anti-cytokine property. Lipopolysaccharide (LPS)-induced or repeated water avoidance stress (WAS)-induced visceral allodynia and increased gut permeability were pro-inflammatory cytokine-dependent responses, which were considered to be animal models of irritable bowel syndrome (IBS). We hypothesized that metformin improves symptoms in the patients with IBS by attenuating these visceral changes and tested the hypothesis in rats. METHODS: The threshold of the visceromotor response induced by colonic balloon distention was measured. Colonic permeability was determined in vivo by quantifying the absorbed Evans blue for 15 min spectrophotometrically. RESULTS: Subcutaneously injected LPS (1 mg/kg) reduced the threshold of visceromotor response, and metformin (5-50 mg/kg for 3 days) intraperitoneally attenuated this response in a dose-dependent manner. Repeated WAS (1 h daily for 3 days) induced visceral allodynia, which was also blocked by metformin. The antinociceptive effect of metformin on the LPS-induced allodynia was reversed by compound C, an adenosine monophosphate-activated protein kinase inhibitor or NG -nitro-L-arginine methyl ester, a nitric oxide synthesis inhibitor but not modified by naloxone. Additionally, it was blocked by sulpiride, a dopamine D2 receptor antagonist, but domperidone, a peripheral dopamine D2 receptor antagonist, did not alter it. Metformin also blocked the LPS-induced or repeated WAS-induced increased colonic permeability. CONCLUSIONS: Metformin attenuated the visceral allodynia and increased gut permeability in animal IBS models. These actions may be evoked via activation of adenosine monophosphate-activated protein kinase, nitric oxide, and central dopamine D2 pathways. These results indicate the possibility that metformin can be useful for treating IBS.


Assuntos
Azul Evans/metabolismo , Hiperalgesia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Mucosa Intestinal/metabolismo , Síndrome do Intestino Irritável/fisiopatologia , Metformina/uso terapêutico , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Animais , Colo/metabolismo , Modelos Animais de Doenças , Domperidona/farmacologia , Antagonistas de Dopamina/farmacologia , Hiperalgesia/etiologia , Hipoglicemiantes/farmacologia , Síndrome do Intestino Irritável/induzido quimicamente , Lipopolissacarídeos , Masculino , Metformina/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Nociceptividade/efeitos dos fármacos , Permeabilidade/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Estresse Fisiológico , Sulpirida/farmacologia
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